Spontaneous somatic mutant frequencies and mutational spectra at the hypoxanthine - guanine phosphoribosyl transferase (hprt) locus in human T- lymphocytes show a strict age dependency from birth to adults (Mut. Res. 1994). To date, no studies have evaluated spontaneous somatic mutant frequencies (MF) in preterm infants. We determined the MF at the hprt locus in preterm infants between 26 and 36 weeks gestation at the time of delivery. A maternal questionnaire, review of the maternal medical record, and determination of plasma cotinine levels were also conducted. History of passive/active cigarette smoke exposure during pregnancy, exposure to medications, and exposure to excessive radiation were evaluated during pregnancy and compared to MF. Infants with known genetic syndromes, major systemic illness or major congenital anomalies were excluded. The cloning efficiency and MF were determined using the hprt T-cell cloning assay, the most widely used assay for determining the frequency and mutational spectra of spontaneous and genotoxic induced somatic genetic mutations in humans. Cord blood samples were obtained from 48 infants, of which 25 were included in the MF analysis. Reasons for non-inclusion were clotted blood (4), insufficient number of cells (6), and no identifiable mutants (13). MF data was obtained from subjects with a mean gestational age of 31.8 weeks. No significant radiation exposure or exposure to genotoxic medications were reported. Medication exposure during pregnancy consisted of, terbutaline, magnesium sulfate, and betamethasone. There were 4 mothers with a history of active/passive cigarette smoke exposure based on questionnaire data. The mean MF for all subjects was 3.44 x l0-6 + 0.44 x l0-6 which is significantly higher than the mean MF in term infants, 1.18 x 10-6 + 0.07 x 10-6. The elevation in mean MF in preterm infants does not appear to be the result of maternal exposures. The MF data obtained demonstrates premature infants have a higher MF than term infants. The elevation in MF may reflect an increase in mutations in rapidly dividing lymphoid cells that subsequently undergo apoptosis prior to 38 weeks gestation. These observations suggest that lymphoid cells in the developing fetus may be at a higher risk of obtaining somatic mutations spontaneously or as a result of genotoxic exposure.